Neuroscience and Biobehavioral Reviews 28 (2004) 395–414

www.elsevier.com/locate/neubiorev

Review
Interactions between the cardiovascular and pain regulatory
systems: an updated review of mechanisms
and possible alterations in chronic pain
Stephen Bruehl*, Ok Yung Chung
Department of Anesthesiology, School of Medicine, Vanderbilt University, 324 Medical Arts Building,
1211 Twenty-First Avenue South, Nashville, TN 37212, USA
Received 1 February 2004; revised 16 June 2004; accepted 16 June 2004

Abstract
Endogenous pain regulatory system dysfunction appears to play a role in the maintenance of chronic pain. An important component of the
pain regulatory process is the functional interaction between the cardiovascular and pain regulatory systems, which results in an association
between elevated resting blood pressure (BP) and diminished acute pain sensitivity. This BP/pain sensitivity relationship is proposed to
reflect a homeostatic feedback loop helping restore arousal levels in the presence of painful stimuli. Evidence is emerging that this normally
adaptive BP/pain sensitivity relationship is significantly altered in chronic pain conditions, affecting responsiveness to both acute and chronic
pain stimuli. Several mechanisms that may underlie this adaptive relationship in healthy individuals are overviewed, including endogenous
opioid, noradrenergic, and baroreceptor-related mechanisms. Theoretical models are presented regarding how chronic pain-related
alterations in the mechanisms above and increased pain facilatory system activity (central sensitization) may contribute to altered BP/pain
sensitivity interactions in chronic pain. Clinical implications are discussed.
q 2004 Elsevier Ltd. All rights reserved.

Keywords: Pain; Acute pain; Chronic pain; Blood pressure; Cardiovascular; Endogenous opioid; Noradrenergic; Alpha-2 adrenergic; Dysfunction

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

2. The relationship between blood pressure and acute pain sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3. Mechanisms underlying the relationship between blood pressure and acute pain sensitivity . . .. . . .. . . .. . .. . . 397
3.1. Structural interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . .. . .. . . 397
3.2. Role of baroreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . .. . .. . . 398
3.3. Endogenous opioid mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . .. . .. . . 399
3.4. Noradrenergic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . .. . .. . . 399

4. Alterations in the blood pressure/pain sensitivity relationship associated with persistent pain . . . . . . . . . . . . . . . . 400
4.1. Effects of prolonged acute pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
4.2. Effects of clinical chronic pain on blood pressure/pain interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

* Corresponding author. Tel.: C6159361821; fax: C6153436272.

E-mail address: stephen.bruehl@vanderbilt.edu (S. Bruehl).

0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2004.06.004
396 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414

5. Possible contributors to chronic pain-related alterations in the blood pressure/pain sensitivity relationship . . . .. . 402
5.1. Impaired descending inhibitory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 402
5.2. Increased descending facilatory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 403
5.3. Alterations in baroreceptor sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 403
5.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 404

6. Possible theoretical models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

7. Methodological and interpretive issues in use of alpha-2 adrenergic blockade methodology . . . . . . . . . . . . . . . . . 406

8. Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

1. Introduction
The ability to adapt effectively to both acute and
persistent pain stimuli is an important contributor to quality
of life. Adaptation to pain is determined by a complex
endogenous pain regulatory system composed of both
descending inhibitory and descending facilatory pathways
[1]. Activity within this system is dependent on duration of
pain stimuli, and functions to maximize survival [1,2].
The initial response to nociceptive stimuli engages
descending inhibitory mechanisms that allow the organism
to escape the injury-causing event (e.g. attack) without
experiencing intense pain sensations that might interfere
with immediate survival [1,2]. After the acute danger has
passed, the pain regulatory system shifts to a relative
predominance of descending facilitation, making pain more
salient as a signal to avoid additional injury and to allow
healing [1,2]. If pain persists beyond this initial healing
period, descending inhibitory pathways display
progressively increased activity to facilitate resumption of
normal activities required for survival [1].
While the above process is adaptive, the development of
chronically painful conditions is clearly maladaptive.
Numerous authors have proposed that chronic pain
develops when ongoing nociceptive stimulation results in
failure of descending pain inhibitory mechanisms [1–6].
In such circumstances, continued activation of descending
pain facilatory mechanisms that sensitize the spinal
nociceptive processing pathways may overwhelm the
exhausted inhibitory system, leading to a chronic
dysfunctional pain state [1,7].
This review will focus on one important component of
the pain regulatory process: the functional interaction
between the cardiovascular and pain regulatory systems
(see Ref. [8], for a general review). This functional
interaction is reflected in the relationship between elevated
resting blood pressure (BP) levels and diminished acute pain
sensitivity that is reliably observed in normotensive humans
(e.g. Refs. [9–16]). It has been proposed that this adaptive
cardiovascular/pain regulatory relationship reflects a
homeostatic feedback loop that helps restore arousal levels
in the presence of painful stimuli [4,8,17].
Nearly all published studies of the relationship between
resting BP and acute pain sensitivity have used brief
experimental pain stimuli in healthy or hypertensive
subjects. However, until recently, the important question
of whether these adaptive cardiovascular/pain regulatory
interactions function normally in the context of chronically
painful conditions had been largely neglected. As will be
detailed below, recent work regarding this issue suggests
that there may be substantial alterations in the BP/pain
sensitivity relationship in chronic pain sufferers [18–20].
Identifying the source of these changes will provide
important clues for understanding the processes
contributing to pain regulatory dysfunction in chronic pain.
2. The relationship between blood pressure
and acute pain sensitivity
Research initially focused on understanding the
hypoalgesia associated with hypertension [21–24] has
highlighted the importance of interrelationships between
the cardiovascular and pain regulatory systems. Even in the
absence of clinical hypertension, familial risk for
hypertension in healthy individuals appears to be associated
with diminished responsiveness to acute pain apart from the
influence of actual BP levels [25–31]. There is suggestive
evidence that these effects are mediated in part by
elevated central descending pain inhibitory activity
(e.g. Refs. [28,29]). Although these studies might suggest
that BP-related hypoalgesia is specifically associated with
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
central mechanisms contributing to hypertension risk, other
studies have demonstrated that regardless of hypertension
status, elevated resting BP levels are associated
with decreased pain sensitivity in healthy normotensive
individuals [9–16]. Correlational analyses further indicate
that this relationship is linear across the normotensive BP
range [9,11]. The BP/pain sensitivity relationship does
appear to be of clinical relevance, given that presurgical
resting systolic BP is inversely associated with acute
postsurgical pain intensity [32].
Although the data are not yet entirely clear, it appears
that while the exaggerated hypoalgesia associated with
hypertension risk may be a marker for central
pathophysiological mechanisms contributing to
hypertension development, the BP/pain sensitivity
relationship in healthy normotensives appears to serve
an adaptive homeostatic function. The mechanisms
underlying this adaptive BP/pain sensitivity relationship
appear complex. The following review will focus on
three possible mechanisms: baroreceptor-mediated
processes, endogenous opioid activity, and noradrenergic
activity. While the first two of these mechanisms have
been evaluated in both animals and humans, this latter
noradrenergic mechanism has received no previous test
in humans. Because this latter mechanism has
received relatively less research attention, this review
will focus particularly on issues regarding possible
noradrenergic mediation of the BP/pain sensitivity
relationship.
Fig. 1. Schematic representation of brain pathways known to be involved in descending pain modulation and blood pressure control. Arrows indicate direction
of neuronal circuits. Sites with known alpha-2 (a-2) adrenergic receptors or norepinephrine (NE) neurons involved in pain and/or cardiovascular modulation
are marked. SNS, sympathetic nervous system.
397
3. Mechanisms underlying the relationship between
blood pressure and acute pain sensitivity
3.1. Structural interactions
The relationship between resting BP and pain sensitivity
arises from what has been described as a central autonomic
network, reflecting integrated brain regions that coordinate
responses to environmental stimuli [8]. The brain regions
underlying control of the cardiovascular system are
known to overlap substantially with those contributing to
antinociception [17]. Fig. 1 summarizes the current
literature with regard to brain pathways that may underlie
the BP/pain sensitivity relationship. Given the particular
focus of the current review on noradrenergic mechanisms,
areas with known alpha-2 adrenergic receptors and/or
norepinephrine-containing neurons are noted.
Of particular interest is the nucleus tractus solitarius
(NTS), which serves as the interface between autonomic
and sensory systems, and is the location of the first synapse
in the baroreceptor reflex pathway [17]. The NTS plays an
important role in the processing of visceral information,
receiving major afferent input from both the vagus nerve
(subserving the baroreflex) and spinal laminae involved in
nociceptive processing [17]. Participation of the NTS in
pain regulatory pathways is evidenced by the fact that
stimulation of the NTS induces antinociception [33].
Antinociception elicited by activation of the NTS may
derive in part from its direct and indirect efferent projections
398 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
to the periaqueductal gray (PAG) and other brain structures
such as the nucleus raphe magnus (NRM) and rostral
ventrolateral medulla (RVM) that are known to be involved
in modulation of pain pathways [1,17,34–37]. In addition to
the brain regions above, efferent projections from the NTS
to the A5 nuclei and A6 nuclei (locus coeruleus, LC) of the
medulla may be important contributors to BP-related
antinociception, given that direct stimulation of these
regions elicits analgesia [38–40]. Interconnections between
the NTS and the LC may be particularly important in
mediating nonopioid analgesia, given that the LC is a
primary source of noradrenergic neurons in the neuraxis
[17]. Pathways from the NTS to spinal cord nuclei
modulating cardiovascular tone, including sympathetic
(intermediolateral cell column) and parasympathetic
preganglionic nuclei, also interact with descending
pain modulation pathways and may be important to consider
[1,41,42]. Thus, through a baroreceptor feedback
loop, descending pain inhibitory pathways may be able to
self-regulate their activity through actions in autonomic
centers of the spinal cord modulating cardiovascular
function [1].
3.2. Role of baroreceptors
A functional model of the BP/pain sensitivity
relationship has been proposed in which: (1) pain, through
a somatosensory reflex, increases sympathetic arousal
producing increased BP, (2) increased BP leads to increased
baroreceptor stimulation, which (3) triggers descending
pain inhibitory activity, thereby helping to return arousal
levels to a state of homeostasis [8,43]. This functional
model presumes a significant role for baroreceptor
activation in the relationship between resting BP and
acute pain sensitivity [17,22,44].
In addition to the structural links described above
between baroreceptor and antinociceptive pathways,
numerous experimental studies support a role for
baroreceptors in the observed relationships between BP
and pain sensitivity. This support derives from several lines
of evidence. First, direct electrical stimulation
of baroreceptor (vagal) afferents induces antinociception
[45,46], as does pharmacologic stimulation of baroreceptor
afferents [17]. In addition, surgical denervation of
baroreceptor afferents eliminates the hypoalgesia induced
by pharmacological pressor agents [47], eliminates the
hypoalgesia displayed by spontaneously hypertensive and
experimentally hypertensive rats [22,48], and produces
hyperalgesia in normotensive animals [22]. A second line of
evidence comes from animal studies indicating that
increases in baroreceptor stimulation resulting from
experimental hypertension induced by social isolation [49]
or renal clip application [23,24] result in significant
hypoalgesia. Finally, experimental data in normotensive
humans also support a role for baroreceptors in mediating
the relationship between resting BP and acute pain
sensitivity. In a naturalistic methodology, spontaneous BP
increases during stressful tasks resulting in elevated
natural baroreceptor stimulation produce diminished pain
sensitivity [50,51]. Furthermore, direct stimulation of
baroreceptors using experimental methodology
(e.g. application of phase-related external suction to carotid
artery) produces diminished acute pain sensitivity [52–58].
It should be noted that the effects of baroreceptor
stimulation on pain responsiveness are likely to impact on
both the sensory and affective components of pain.
Experimental stimulation of baroreceptors results not only
in decreased sensory acute pain intensity, but also
diminished sympathetic nervous system reactivity [56],
one indicator of affective pain intensity [59].
The issue of baroreceptor resetting must be addressed in
discussions of this potential mechanism. Persistent
baroreceptor stimulation related to BP elevations lasting
from a few minutes to a few days may result in a resetting of
baroreceptors [60,61]. It is believed that the BP set point
around which the baroreflex is centered is increased, and the
BP threshold required to trigger baroreceptor activation is
therefore increased [63]. It should be noted that while much
evidence exists that such resetting occurs, support for this
concept remains somewhat mixed. For example, recent
work in dogs indicated that chronic activation of
carotid baroreceptors over seven days produced prolonged
sympathetic inhibition and diminished BP throughout this
period [62]. If baroreceptors do not, in fact, reset after
sustained BP elevations, this issue would not appear to
impact significantly on understanding the relationship
between resting BP and pain sensitivity. However, to the
extent that baroreceptor resetting does occur after prolonged
BP elevations, this might raise questions as to how
presumably stable resting BPs would be associated with
diminished pain sensitivity if baroreceptor mechanisms
were involved. Recent work suggests the possibility that
the key issue may not be the degree of tonic baroreceptor
stimulation, but rather, the degree of phasic
baroreceptor stimulation related to the cardiac cycle.
Edwards et al. [64,65] found that sensitivity to very brief
electrical pain stimuli among normotensive humans covar-
ied with the cardiac cycle, with subjects displaying the
lowest pain sensitivity during systole and the greatest pain
sensitivity during diastole. In light of the fact
that baroreceptors may not be tonically stimulated at
normotensive systolic pressures and therefore would not
reset [67], natural phasic baroreceptor stimulation occurring
with systole may account for the observed inverse
relationship between resting BP and pain sensitivity.
Thus, in normotensives, higher systolic pressure elevations
might produce greater baroreceptor activation, and thus
greater antinociceptive activity, with little effect of diastolic
pressure levels. Consistent with this proposal,
numerous studies have reported a greater effect size for
systolic BP on pain sensitivity than is observed for diastolic
BP (e.g. Refs. [9–11,16,26,30,32,67–69]). Taken together,
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
the data above would support baroreceptor activity as
a likely contributor to the resting BP/pain sensitivity
relationship in normotensives. A role for baroreceptors in
this relationship supports the concept that this relationship
reflects a homeostatic feedback system, at least in healthy
normotensive individuals.
3.3. Endogenous opioid mechanisms
One important neurochemical substrate of
descending pain inhibitory pathways is endogenous opioid
activity [1,4]. A role for endogenous opioids in expression
of the BP/pain sensitivity relationship has been shown in
numerous animal studies. For example, decreased pain
sensitivity associated with hypertension [22–24,49,70–72]
is reversible with pharmacological opioid blockade.
These animal studies, all of which addressed presence/
absence of hypertension rather than resting BP levels in
normotensive animals, are consistent with the idea that
endogenous opioid activity may be necessary for full
expression of the inverse relationship between BP and
pain sensitivity.
Human studies, in contrast, provide weaker support for
opioid mechanisms. Several studies have reported that
elevated BP was associated with both lower levels of pain
sensitivity and increased plasma levels of beta-endorphin, a
potent endogenous opioid analgesic [73–75]. However, it is
unclear whether these elevated levels of beta-endorphin
mediated the BP/pain sensitivity relationship, given
evidence that beta-endorphin levels were not significantly
associated with degree of pain responsiveness [74].
More recent work in normotensives examining
plasma levels of beta-endorphin also failed to
support opioid mediation of the BP/acute pain relationship
[19]. In summary, findings of studies assaying plasma
levels of opioids are mixed regarding opioid mediation of
the BP/pain association in humans. Presence of clinical
hypertension could be an importance consideration in
interpreting these studies, given that two of the three studies
showing elevated circulating endogenous opioid levels in
association with both elevated BP and diminished pain
responsiveness were obtained using designs comparing
hypertensive to normotensive subjects [73,74].
This interpretation would be consistent with support for
opioid mechanisms derived from numerous animal studies
comparing hypertensive to normotensive animals.
Work using opioid blockade methodology in humans has
consistently failed to support a significant role for
endogenous opioids in mediating the BP/pain relationship.
Among both normotensive [11,76] and borderline
hypertensive males [76], naloxone failed to alter
significantly the inverse association between resting BP
and pain sensitivity to cold pressor or electrical pain stimuli.
More recent results from our lab further indicate that opioid
blockade with naloxone does not significantly alter the
inverse relationship between resting BP and both ischemic
399
and pressure pain sensitivity in pain-free normotensive
males or females [10]. It should be noted, however, that
none of these blockade studies were conducted in clinically
hypertensive samples.
In light of the strong animal evidence for opioid
mechanisms using opioid blockade methodology,
this failure to support opioid mechanisms in humans is
somewhat surprising. McCubbin and Bruehl [11] found that
the simple correlation between resting systolic BP and pain
sensitivity was reduced by naloxone from K0.54 to K0.11,
suggesting initially at least partial opioid mediation.
However, examination of the simple correlations between
BP and pain ratings across placebo/naloxone conditions
may be somewhat misleading. When multiple regression
was conducted controlling for main effects of BP and drug,
there was no significant drug X BP interaction on pain.
A similar nonsignificant interaction was noted in our recent
work [10]. Interaction effect sizes for these nonsignificant
findings are small, with a hypothetical tripling in
sample size still not being sufficient to produce a significant
opioid-mediation effect [10]. In light of similar negative
findings in the only other relevant opioid blockade study
[76], the evidence suggests that the BP/pain sensitivity
relationship can occur independently of opioid-mediated
mechanisms in normotensives. Despite the negative results
of blockade studies conducted to date, the strength of
the animal literature supporting opioid mechanisms and the
relative paucity of human studies addressing this
issue would suggest that the role of endogenous opioids in
the BP/pain sensitivity relationship may best be considered
an open question. The human data above would suggest that
a role for endogenous opioids should be further investigated
particularly with regard to hypertensive populations.
In summary, while animal studies suggest that
endogenous opioid mechanisms are important, results of
human studies suggest that the BP/pain sensitivity
relationship can occur in normotensives even in the absence
of functionally active endogenous opioid systems.
This pattern of findings highlights the potential importance
of examining nonopioid mechanisms that could contribute
to this adaptive relationship in normotensive humans.
3.4. Noradrenergic mechanisms
A primary nonopioid mechanism to consider is
noradrenergic activity. Central noradrenergic pathways,
particularly those mediated by alpha-2 adrenoceptors, are
a crucial component of the descending pain inhibitory
system [1,77,78]. Complex interactions between several of
the brain regions described above may lead to
adrenergically mediated antinociception [79] (see Fig. 1).
For example, it is believed that nociceptive stimulation
directly activates the RVM, triggering excitatory
neurotransmitters that increase norepinephrine release
from the LC, thus activating descending noradrenergic
pathways leading to antinociception mediated by spinal
400 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
alpha-2 inhibitory adrenergic receptors [79]. The specific
role of alpha-2 adrenergic activity in descending
nociceptive inhibition is evidenced experimentally by:
(1) clinical use of alpha-2 agonists as analgesics [80,81];
(2) ability of such agents to produce analgesia through
supraspinal mechanisms [82,83]; (3) the effects of several
analgesic agents can be eliminated by selective alpha-2
adrenergic receptor blockade [82–86], and (4) acute pain
responses are increased following selective alpha-2
adrenergic blockade [87–89]. Limited human data also
supports the role of alpha-2 adrenergic mechanisms in
endogenous pain modulation. Intravenous yohimbine,
a selective alpha-2 adrenergic antagonist, resulted in
significant increases in self-reported pain in response to an
experimental rectal distension pain stimulus [90,91].
Pilot data in a small sample of healthy subjects examined
in our lab further support these findings, indicating that
intravenous yohimbine resulted in a significant 18%
increase in mean pain intensity ratings obtained during an
ischemic laboratory pain task (unpublished data).
The composite yohimbine effect size across all pain rating
measures obtained and across ischemic and finger pressure
pain tasks was rZ0.42, indicating a moderate-sized
hyperalgesic effects of yohimbine in humans (unpublished
data). These data support an important role for
noradrenergic mechanisms in human endogenous pain
regulatory systems.
Central noradrenergic pathways are also known to
be important in cardiovascular regulation [92,93].
For example, noradrenergic projections from the LC to the
NTS have been shown to be involved in baroreceptor-
mediated neurotransmission [93,94]. In particular, activity
at alpha-2 adrenergic receptors appears to be an important
modulator of the baroreceptor reflex, as evidenced by
altered baroreflex responses following selective alpha-2
blockade [93,95–97].
Overlap in noradrenergic pathways underlying both
cardiovascular regulation and pain transmission is
apparent. Given the important role of the NTS as an
interface for cardiovascular and pain regulation [17], it is
notable that significant populations of alpha-2 adrenergic
receptors are located within the NTS [98]. Other
areas described above as being structurally important in
cardiovascular/pain regulatory relationships, such as the
NRM, PAG, the RVM, and the LC are all sources
of noradrenergic influences on descending pain
modulation, particularly through alpha-2 adrenoceptor
activity [1,8,17,38,40,99–102]. Thus, the interlinked brain
structures underlying both cardiovascular regulation and
descending pain inhibition have large populations of
noradrenergic fibers and alpha-2 adrenergic receptors that
impact on both BP and antinociception.
Based on these findings, alpha-adrenergic activity has
been proposed to be a contributor to the functional
relationship between BP and acute pain sensitivity [17].
Animal studies provide support for this hypothesis.
Analgesia resulting from activation of baroreceptors can be
eliminated by blockade of alpha adrenergic receptors [17].
Moreover, hypertension is associated with antinociception
reversible with adrenergic receptor blockade [48,70].
Chemical lesioning of the brainstem noradrenergic system
has also been shown to eliminate the hypoalgesia associated
with spontaneous hypertension [103]. These latter findings
suggest an important role for supraspinal alpha-2 adrenergic
descending pathways in mediating BP-related analgesia.
Other evidence for adrenergic involvement in baroreceptor-
mediated analgesia comes from work indicating that
pharmacological blockade of adrenergic receptors signifi-
cantly attenuates the hypoalgesia resulting from direct
stimulation of vagal baroreceptor afferents [104]. In humans,
a possible role for alpha-2 adrenergic mechanisms in the
BP/pain sensitivity relationship is indirectly suggested by
work indicating that normotensive subjects with higher BP
exhibited both increased electrical pain tolerance
and elevated circulating levels of norepinephrine
(an endogenous alpha-2 agonist), although mediation was
not directly tested [75]. Work suggesting that noradrenergic
mechanisms contribute significantly to baroreceptor-
mediated analgesia is likely to account for the failure of
opioid blockade to eliminate the hypoalgesia resulting from
experimental stimulation of baroreceptor pathways [105],
and its failure to significantly attenuate the relationship
between resting BP and pain sensitivity in normotensive
humans [10,11,76].
In summary, there is much direct and indirect evidence
from animal research that alpha-2 adrenergic mechanisms
may contribute to the relationship between BP and pain
sensitivity. Although the lack of human data on this issue
makes direct evaluation of the relative merits of opioid versus
alpha-2 adrenergic hypotheses difficult, both theory and
animal work would suggest that examination of alpha-2
adrenergic mechanisms in humans may represent a fruitful
line of inquiry. This review will now turn to the issue of
chronic pain-related alterations in the adaptive relationship
between BP and acute pain sensitivity, and will highlight
several possible mechanisms that may underlie these
alterations.
4. Alterations in the blood pressure/pain sensitivity
relationship associated with persistent pain
4.1. Effects of prolonged acute pain
Nearly all studies of the BP/pain sensitivity relationship,
animal and human, have used brief experimental acute pain
stimuli (typically !5 min in duration). The importance of
pain duration as a potential moderator of this relationship is
suggested by three animal studies that have examined the
BP/pain sensitivity relationship in the context of more
prolonged acute pain stimuli. Injection of formalin into rat
paws was used to produce prolonged (90 min) inflammatory
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
pain [103,106,107]. While hypertensive rats as expected
exhibited lower pain sensitivity relative to normotensive
rats to brief acute pain tests (e.g. hotplate test, paw
pressure), hypertensives displayed greater pain sensitivity
to the more prolonged formalin pain task relative to
normotensives [103,106,107]. These results would be
consistent with an inverse relationship between resting BP
levels and sensitivity to brief acute pain stimuli as has been
found in numerous other studies, but a significant positive
relationship between resting BP and pain sensitivity to more
prolonged acute pain stimuli. The multiphasic pain
regulatory response described above [1] might lead one to
predict alterations in the pattern of the BP/pain relationship
dependent upon pain duration like those observed in the
studies above. For example, elevated BP might be
associated with enhanced activation of pain inhibitory
pathways in the context of brief pain, but might also be
associated with greater activation of pain facilatory
pathways in response to more prolonged pain. Although
comparable human data are not available, these results do
suggest that it may be important to consider BP/pain
sensitivity interactions not as an invariant phenomenon,
but rather, part of a plastic, adaptive process that may
change with ongoing nociceptive input. Studies in clinical
chronic pain conditions highlight the importance of this
latter consideration.
4.2. Effects of clinical chronic pain on blood
pressure/pain interactions
Limited work in human chronic pain samples suggests
that chronic pain is associated with significant alterations in
the relationship between resting BP and acute pain
sensitivity. In contrast to the significant inverse relationship
observed in pain-free individuals, Maixner et al. [20]
reported that resting BP was unrelated to responsiveness
to ischemic or thermal acute pain stimuli among orofacial
pain patients. More recent work suggests not simply a
dissociation of BP and acute pain sensitivity, but rather,
a reversal of this normally adaptive relationship in chronic
pain. For example, Bragdon et al. [19] reported a reversal in
direction of the relationship between resting BP and
sensitivity to ischemic and thermal pain stimuli in chronic
orofacial pain sufferers compared to pain-free controls [19].
Previous work in our lab also indicated that the expected
inverse relationship between resting BP and ischemic pain
sensitivity among pain-free controls was significantly
reversed (i.e. positive) among chronic low back pain
sufferers [10]. This effect is best exemplified by ischemic
pain threshold data that are summarized in Fig. 2 below.
Although this figure suggests a possible nonlinear
relationship in the chronic back pain group, data in this
figure reflect post hoc tertile splits on resting systolic BP
levels conducted solely for display purposes. General linear
model analyses confirmed a linear trend for the relationship
between BP levels and pain threshold that was in opposite
401
Fig. 2. Relationship between resting systolic BP and ischemic pain
threshold across chronic pain/pain-free groups. Note: Control, Pain-free
healthy normotensive controls; Pain, Chronic low back pain.
directions across pain-free control and chronic back pain
groups. The likelihood that cardiovascular/pain regulatory
system interactions are altered in individuals with chronic
pain is further underscored by findings that chronic back
pain patients responded to experimental stimulation of
carotid baroreceptors with increased sensitivity to electrical
pain rather than the diminished pain responsiveness
typically reported in pain-free individuals [108].
The positive relationship between resting BP and acute
pain sensitivity in chronic pain patients may reflect general-
ized dysfunction in pain inhibitory systems, given that these
effects extend beyond acute pain responsiveness. Our work in
a low back pain patient sample also indicated a significant
positive relationship between resting BP and ratings of clinical
chronic pain intensity [10]. Other work in a chronic pain
sample displaying diverse pain etiologies similarly reported
resting BP to be positively correlated with clinical pain
intensity [18]. Interestingly, this latter study suggested that the
pain regulatory dysfunction apparently reflected in this
positive BP/chronic pain relationship was progressive, as
might be expected if it were due to gradual exhaustion of pain
inhibitory systems or gradual changes in baroreceptor
function. A statistically significant interaction was detected
between pain duration and resting systolic BP in predicting
ratings of clinical pain. For chronic pain of 6–14 months
duration, the correlation between BP and chronic pain
intensity was rZK0.18 (p>0.10); for 15–28 month duration,
rZ0.14 (p>0.10); and for pain of more than 28 months
duration, rZ0.50 (p!0.001). Thus, while a small inverse
correlation between resting BP and chronic pain intensity was
detected in patients with the shortest chronic pain syndromes,
consistent with the adaptive inverse BP/acute pain
relationship noted in healthy individuals, this relationship
becomes positive and increasingly strong with greater pain
duration.
Overall, available data suggest that the normally inverse
relationship between resting BP and acute pain sensitivity
may be altered in chronic pain conditions, with
consequences for the experience of clinical pain as well.
402 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
The observed alterations in the BP/pain sensitivity
relationship are likely to reflect broader alterations in
endogenous pain regulatory systems related to chronic pain.
As described previously, the pain regulatory system is
composed of both pain inhibitory and pain facilatory
pathways. There is evidence suggesting that activity in
both of these pathways is altered in chronic pain conditions.
Chronic pain-related alterations in both of these pathways
could contribute to the observed alterations in the functional
relationship between BP and pain sensitivity. Changes in
baroreceptor pathways related to chronic pain may also
contribute to altered relationships between BP and pain
sensitivity. Evidence for chronic pain-related changes in
each of these areas will now be overviewed, and the
potential relevance of such changes for cardiovascular/pain
regulatory interactions will be described.
5. Possible contributors to chronic pain-related
alterations in the blood pressure/pain
sensitivity relationship
5.1. Impaired descending inhibitory mechanisms
Descending pain inhibitory pathways appear to display
progressively increased activity if nociceptive stimulation
persists [1,7]. It has been suggested that persistent
and excessive antinociceptive demands may eventually
exhaust these descending inhibitory systems, thereby
contributing to development or maintenance of chronic
pain [1,3,4]. Evidence supporting this antinociceptive
dysfunction hypothesis comes from several sources. Studies
in patients with diverse chronic pain conditions indicate that
chronic pain is often associated with increased experimental
acute pain sensitivity relative to pain-free controls as
assessed by both objective (i.e. brain evoked potentials)
and subjective measures [5,109–114]. Furthermore, chronic
pain patients do not display the progressive adaptation to
repeated pain stimuli observed in pain-free controls [112,
113]. These findings suggest that pain perception may be
enhanced, and pain inhibitory processes impaired,
in chronic pain sufferers.
There is evidence indicating that these changes are due at
least in part to alterations in descending pain inhibitory
pathways. One experimental indicator of descending pain
inhibitory activity is activation of diffuse noxious inhibitory
controls (DNIC) by heterotopic conditioning stimulation
[115]. In pain-free individuals, an intense pain
stimulus applied to one body location results in diminished
responsiveness to pain stimuli applied to multiple
other body regions, presumably reflecting DNIC activation
[5,115]. In patients with chronic osteoarthritis or
fibromyalgia, heterotopic conditioning stimulation fails to
activate DNIC whereas pain-free control subjects exhibit
evidence of DNIC activation [5,6,116]. Interestingly, one
study indicates that surgical correction of the source of
chronic nociceptive input (i.e. hip replacement in
osteoarthritis patients) restored a normal DNIC response
[6]. Taken together, these results suggest that ability to
activate descending pain modulation pathways is impaired
in chronic pain patients, and that dysfunction in these
descending inhibitory pathways is both a consequence of
and a contributor to the chronic pain state [6].
Neural mediators of these chronic pain-related changes
in descending inhibitory mechanisms are likely to include
endogenous opioid as well as nonopioid mechanisms.
Endogenous opioids play an important functional role as
inhibitory neurotransmitters in the antinociceptive system
[1]. It is therefore notable that patients with chronic pain
of a variety of etiologies display lower plasma and CSF
levels of endogenous opioids than do pain-free normals
(see Ref. [4], for a review). This pattern would be
consistent with impairment in opioid-mediated pain
inhibitory pathways in chronic pain sufferers [4].
Opioid blockade studies indicate that opioid-mediated
antinociception to acute pain may be functionally
impaired at least in a subset of chronic pain patients,
and this impairment may also impact on chronic pain
intensity. Work in our lab indicates that failure to elicit
opioid analgesia to acute pain stimuli (as reflected in lack
of response to opioid blockade) was associated with
greater clinical pain in chronic low back pain patients
with higher disability levels [117]. In other words,
endogenous opioid antinociceptive impairment may
contribute to elevated acute and chronic pain sensitivity,
at least among more disabled chronic pain patients.
Central noradrenergic mechanisms also appear to be
crucial for descending pain inhibitory pathways [1,87–89].
Although widely studied in the context of acute pain,
changes in descending noradrenergic inhibitory pathways
associated with chronic pain have been less widely
examined. Animal models indicate decreased dorsal horn
alpha-2 adrenergic receptor density following chronic pain,
a finding consistent with chronic pain-related attenuation of
noradrenergic descending inhibitory capabilities [118].
Consonant with receptor changes mediating impaired
descending alpha-2 pain inhibition, decreased analgesic
responsiveness to alpha-2 agonists is observed in animal
chronic pain models compared to pain-free animals,
indicating possible alpha-2 receptor deficits [119].
In addition to reduced adrenergic receptor density, animal
chronic pain models suggest that up-regulated
norepinephrine turnover in the dorsal horn should also be
considered, given that this process might contribute to
eventual exhaustion of noradrenergic pathways [120].
Human studies provide indirect support for impairments in
descending noradrenergic inhibitory pathways in chronic
pain. Diminished release of beta-endorphin in response to
alpha-adrenergic stimulation has been described in chronic
headache patients relative to pain-free controls [121],
a finding consistent with the receptor changes noted above
[118]. Likely impairments in noradrenergic inhibitory
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
pathways in human chronic pain are also suggested by the
efficacy of pharmacological agents that enhance descending
noradrenergic activity (e.g. tricyclic antidepressants) for
decreasing chronic pain intensity [122,123]. A conceptual
argument could also be made. While descending opioid
and alpha-2 adrenergic pain inhibitory systems are not
conceptually identical, there are obvious parallels in the
factors that might underlie their dysfunction in chronic pain
(i.e. exhaustion through chronic activation; [1]). In the
absence of data indicating otherwise, there are strong
theoretical reasons to believe that chronic pain-related
dysfunction in alpha-2 adrenergic systems would likely
parallel those reported in endogenous opioid systems.
As described previously, increased BP/baroreceptor
activity is associated with activation of descending pain
inhibitory pathways mediated in part by endogenous opioid
and alpha-2 adrenergic mechanisms. Therefore, chronic
pain-related impairments in either of these pathways
might have an impact on expression of the BP/pain
sensitivity relationship. Our recent work suggests that
endogenous opioid mechanisms do not account for chronic
pain-related changes in the BP/pain sensitivity relationship
in normotensives [10]. Specifically, opioid blockade did not
exert a significant interaction effect on differences in the
resting BP/acute pain sensitivity relationship across chronic
pain and pain-free groups [10]. Given the potential
importance of noradrenergic mechanisms in expression of
this relationship in humans, impairments in noradrenergic
inhibitory pathways may be of particular relevance
for understanding chronic pain-related alterations in the
BP/pain sensitivity relationship.
5.2. Increased descending facilatory mechanisms
Both nociceptive and neuropathic pain trigger increased
excitability in spinal cord nociceptive neurons [124].
This central sensitization is an important pathophysiological
mechanism contributing to persistent pain. The clinical
consequences of central sensitization include hyperalgesia
and increased wind-up [125,126]. Wind-up is observed
when nociceptive C-fibers are repeatedly stimulated at a
frequency similar to their natural firing rate (every 2–3 s),
causing a slow temporal summation of this nociceptive
firing [127]. With repeated stimulation of C-fibers at this
rate, even at sub-pain threshold levels, the responses of
nociceptive dorsal horn neurons undergo a progressive
increase [126,127]. As a result, levels of stimulation initially
described as nonpainful are reported to be painful as
temporal summation/wind-up occurs. Central sensitization
processes may be relevant to understanding the BP/pain
sensitivity relationship, given recent evidence that the
hypoalgesia associated with increased hypertension risk
may be mediated in part by diminished triggering of
temporal summation [28]. Given the focus of this review,
it is notable that temporal summation is exaggerated in
individuals experiencing chronic pain, due to the process of
403
central sensitization [114,125,127–129]. The impact of
chronic pain-related central sensitization on the BP/pain
sensitivity relationship is not known, although the
physiological interconnections described below suggest
that it may be an important factor to consider.
Central sensitization is not purely a local phenomenon
occurring at primary afferent fibers [1], but rather, results in
part from descending pain facilatory mechanisms [130].
Brain regions involved in descending pain facilitation
appear to include the PAG [131], the NRM [132], the
NTS [132], and the RVM [133]. For example, lesions in
the NTS and NRM can substantially block development of
central sensitization [132]. While there are multiple
peptides and neurotransmitters mediating the
development of central sensitization, one important factor
is substance P, a peptide acting at the NK1 receptor
[134–137]. Pharmacological blockade of NK1 receptors
or use of genetic ‘knockout’ mice lacking NK1
receptors results in significant reductions in wind-up
phenomena [134–136]. There is evidence that substance P
is involved in central sensitization through descending
facilatory pathways arising from the brain regions above as
well as local release at primary afferent fibers [138,139].
Given the emphasis of this review, it is noteworthy that
baroreceptor activation may trigger not only pain
inhibitory activity but descending pain facilatory activity
as well, possibly through substance P-mediated pathways
[1,3,140,141]. Brain structures believed to be involved in
central sensitization and known to contain substance P
fibers, particularly the NTS and NRM, are also extensively
involved in cardiovascular regulation through
baroreceptor pathways, and appear to be important sites
underlying the BP/pain sensitivity relationship [17,42,132].
Experimental studies indicate that the substance P present in
these baroreceptor pathways is functionally involved in
cardiovascular regulation [142–145].
In summary, reduced temporal summation could
contribute to BP-related antinociception. Chronic pain
activates descending pain facilatory pathways, mediated in
part by substance P, resulting in central sensitization and
increased temporal summation. Substance P pathways and
the brain structures underlying the BP/pain sensitivity
relationship appear to overlap, and substance P has
effects on both pain regulation and baroreflex control of
cardiovascular function. Taken together, these
findings suggest a possible mechanism by which chronic
pain-related activation of pain facilatory pathways might
contribute to alterations in the functional relationship
between BP and pain sensitivity.
5.3. Alterations in baroreceptor sensitivity
Maixner et al. [3] have hypothesized that changes in
baroreceptor sensitivity may contribute to alterations in pain
regulatory processes associated with chronic pain.
Changes in baroreceptor sensitivity may occur due to
404 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
altered threshold for baroreceptor firing or altered central
nervous system gain associated with this firing [17].
The functional consequences of diminished baroreceptor
sensitivity include impaired inhibition of sympathetic
nervous system arousal responses and impaired activation
of parasympathetic nervous system inhibitory responses in
the face of stressful stimuli [17]. To date, the baroreceptor
sensitivity hypothesis has not been subjected to adequate
experimental evaluation. Only one published study
has examined baroreceptor-issues in chronic pain sufferers
[108]. Activation of carotid baroreceptors using phase-
related external suction was found to produce increased
sensitivity to electrical pain stimuli in chronic low back pain
patients [108]. This finding is in contrast to the
numerous studies indicating that similar baroreceptor
manipulation produces analgesia in pain-free normotensives
(see Ref. [53], for a review).
That baroreceptor sensitivity might be altered in chronic
pain would not be unexpected, given that it may be altered
in other disease states and in response to stress.
For example, baroreceptor sensitivity appears to be reduced
in chronic hypertension [146–148]. Decreases in
baroreceptor sensitivity are also associated with increased
anxiety levels [149]. This latter finding highlights the
importance of the proposed concept of central baroreflex
clamping, in which some circumstance (such as increased
sympathetic activation due to fear or anxiety) result in
baroreceptor input being overridden at the limbic or
hypothalamic levels [17]. Consistent with this concept,
a number of human studies suggest that baroreceptor
sensitivity may be decreased in response to acute
experimental stress [150–154]. Moreover, chronic stress in
animals appears to be associated with decreased
baroreceptor sensitivity [155,156]. There is some evidence
that central noradrenergic changes may account for the
reduced baroreceptor sensitivity associated with chronic
stress [155,157]. Taken together, these data indicate that
baroreceptor sensitivity may be diminished in response to
both acute and chronic stress, and therefore, the stress
associated with chronic pain might be expected to lead to
similar diminished baroreceptor sensitivity. To the extent
that baroreceptor stimulation is necessary for expression of
the BP/pain sensitivity relationship, chronic pain-related
reductions in baroreceptor sensitivity might help explain
chronic pain-related alterations in this relationship.
Possible interactive effects of substance P and alpha-2
adrenergic activity in baroreceptor-mediated cardiovascular
regulation, combined with chronic pain-related changes in
pathways mediated by these neurochemicals, might
also suggest a role for baroreceptor changes in the altered
BP/pain sensitivity relationship in chronic pain.
One potential limitation to the arguments above should
be noted. While the relationship between stress-related
reductions in baroreceptor sensitivity and alterations in pain
sensitivity has not been examined, there exists a clear
paradox with regards to hypertension. Specifically, there is
good evidence that clinical hypertension is associated
with diminished baroreceptor sensitivity [146–148],
yet hypertension is also clearly associated with diminished
pain sensitivity despite this decreased baroreceptor
sensitivity. Reconciling this fact with other evidence,
primarily in normotensives, that experimental baroreceptor
activation produces analgesia (and the converse) is difficult,
although the possibility is raised that multiple potential
pathways (baroreceptor, opioid, norepinephrine, and others)
could lead to the inverse BP/pain sensitivity relationship
under different conditions. Resolution of such issues must
await future work.
5.4. Summary
The studies reviewed above indicate that: (1) the
functional relationship between BP and pain sensitivity
is an important part of the pain regulatory process,
(2) baroreceptor-mediated pathways and alpha-2 adrenergic
activity may contribute to expression of this relationship in
normotensives, (3) the BP/pain sensitivity relationship is
significantly altered in normotensive chronic pain sufferers,
and (4) endogenous opioid mechanisms are not required to
account for these alterations. Based on brain structural
studies, experimental animal work, and theoretical
considerations, it is proposed that chronic pain-related
alterations in the BP/pain sensitivity relationship could be
due to changes in baroreceptor sensitivity, impairments in
descending noradrenergic pain inhibitory pathways, and/or
activation of pain facilatory pathways. Several possible
theoretical models detailing how these mechanisms could
lead to a positive relationship between resting BP and both
acute and chronic pain responsiveness will now be
described.
6. Possible theoretical models
Several theoretical models (not mutually exclusive)
could help explain the alterations in the BP/acute pain
sensitivity relationship observed in chronic pain patients.
Model 1 is based on the finding that nociceptive input
triggers a direct somatosympathetic reflex elevation in BP
[36,158]. If persistent nociceptive input leads to failure of
descending alpha-2 adrenergic inhibitory systems
contributing to the inverse BP/pain sensitivity relationship,
direct SNS-mediated BP increases may predominate in
chronic pain. In the presence of inhibitory failure, resting
BP would be expected to increase as clinical pain intensity
(and related SNS arousal) increased. Thus, chronic pain
would lead concurrently to failure of descending
pain inhibitory systems and direct SNS-mediated BP
increases. This pattern would result in a positive
relationship between resting BP and both acute pain
sensitivity and chronic pain intensity in chronic pain
patients, a finding we have reported previously [10,18].
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
In addition, Model 1 would predict relatively greater SNS
arousal in chronic pain patients.
Evidence to support elevated SNS arousal in chronic
pain patients comes from several sources. Of greatest
relevance to this review are cardiovascular indices that
reflect SNS arousal, including BP and heart rate
[159–161]. Chronic pain patients with myofascial pain,
orofacial pain, and arthritic pain all display greater resting
heart rates than do pain-free healthy controls [3,162].
Given the focus of the current review, the strongest
indirect support for Model 1 would derive from studies
indicating elevated BP in chronic pain patients. Although
data from prior work in our lab cannot be used to address
this issue because samples were preselected for normo-
tensive status [10,18], work of other investigators in
nonpreselected samples does suggest elevated resting BPs
in persistent pain sufferers. In a well-designed laboratory
study, chronic low back pain patients were found to
display significantly higher mean diastolic BP
(79 mm Hg) than did pain-free controls (71 mm Hg)
[108]. Work in the primary care setting has also indicated
that patients suffering from widespread chronic pain
display higher resting systolic BP levels (133 mm Hg)
than do pain-free patient controls (120 mm Hg) [163].
Also relevant is work indicating that retail cashiers
experiencing persistent shoulder pain displayed higher
mean resting systolic and diastolic BP levels than age-
matched cashiers not experiencing pain [164]. Not only do
resting cardiovascular parameters appear to be elevated in
chronic pain sufferers, but so does cardiovascular
reactivity. Carlson et al. [165] reported that chronic
orofacial pain patients displayed significantly greater
systolic BP and heart rate levels during a mental stressor
than did pain-free age and sex-matched controls. Maixner
et al. [3] reported similarly elevated heart rate reactivity
to stress in chronic orofacial pain patients relative to
pain-free controls.
Another possible index of excessive SNS activity in
chronic pain patients may be the presence of clinical
hypertension. There is substantial evidence that
hypertension is associated with elevated SNS arousal
[166–171]. Recent clinical research may therefore
be relevant regarding this issue [172]. We compared
the prevalence of clinical hypertension and use of
antihypertensives in randomly selected samples of 300
tertiary care chronic pain patients and 300 nonpain internal
medicine patients. Results indicated that 39% of the
chronic pain sample was diagnosed with clinical hyper-
tension compared to only 21% of the internal medicine
sample, with parallel results regarding antihypertensive use
(p’s!0.001). In light of the work cited above, these
findings would be consistent with chronic pain patients
experiencing chronically elevated SNS activity and would
support Model 1.
Cardiovascular parameters are not the only indices
suggesting elevated SNS activity in chronic pain patients.
405
Previous work indicates that chronic low back pain patients
and chronic arthritic pain patients display a significantly
higher baseline electrodermal response and greater
electrodermal reactivity to laboratory stressors than is
observed in pain-free controls [162,173,174]. This increased
electrodermal response indicates elevated sympathetic
(sudomotor) arousal [175–176]. Based on tests of
autonomically mediated pupillary light reflexes, Perry
et al. [162] have also reported evidence for elevated central
sympathetic drive in chronic myofascial pain patients
relative to pain-free controls. Finally, work examining
overnight urinary catecholamines indicates elevated levels
in chronic myofascial pain patients relative to pain-free
controls [177], also supporting elevated sympathetic/
adrenergic activity in these patients.
In summary, a number of studies using different indices
of sympathetic arousal are consistent with the presence of
elevated SNS activity in chronic pain patients. The limited
controlled work in humans addressing BP levels in
chronic pain patients and pain-free controls is consistent
with the predictions of Model 1 that chronic pain is
associated with increased SNS drive and consequently
elevated resting BP.
The mechanism described in Model 1 also implies some
degree of cardiovascular baroreflex failure; otherwise, direct
SNS-mediated increases in BP would trigger
baroreflex mechanisms that would restore pressures to
lower levels (and lead to an inverse BP/pain relationship).
In fact, some work suggests that stress produces an opposing
interaction between direct SNS-mediated pressor responses
and baroreflex-mediated depressor responses, with the
balance of these two processes determining BP levels
[178]. It may therefore be important to consider baroreceptor
sensitivity if chronic pain-related alterations in the BP/pain
sensitivity relationship are to be fully understood (Model 2).
For example, in the absence of functioning baroreflex
mechanisms (due to baroreceptor deafferentation),
increasing stress results in increased SNS activity and
increased BP [179]. To the extent that baroreceptor
activation accounts for the BP/pain sensitivity relationship,
significantly diminished baroreceptor sensitivity among
chronic pain patients might eliminate the normally observed
relationship between BP and pain sensitivity. Therefore, in
the absence of baroreceptor-mediated pain inhibition and
presumably impaired baroreflex-mediated cardiovascular
depressor responses, the direct pressor effect of pain
on BP (through somatosympathetic reflex activation)
may predominate, and lead to the positive BP/pain
correlation observed in chronic pain patients. Given the
role of alpha-2 adrenergic mechanisms in the baroreflex
loop [180], the adrenergic dysfunction described
above would likely be involved in these baroreceptor
changes. If the mechanisms in Model 2 are operative,
experimental studies should demonstrate that the degree
of alteration in the BP/pain sensitivity relationship across
chronic pain/pain-free subjects is accounted for by the degree
406 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
of reduction in baroreceptor sensitivity associated with
chronic pain. To date, this hypothesis has not been directly
tested.
A third mechanism may be important as well. Animal
work by Taylor et al. [103] found that elevated BP was
associated with increased noradrenergically mediated
antinociception in response to brief acute pain, but impaired
noradrenergic antinociception in response to more
prolonged acute pain. Consistent with these changes in the
BP/pain sensitivity relationship as a function of pain
duration, the only human study addressing baroreceptor
issues in persistent pain states indicated that direct
stimulation of baroreceptors resulted in relative increases
in pain sensitivity among chronic pain patients,
in contrast to the decreased pain sensitivity typically
observed in pain-free subjects [108]. These findings may
be explained by the fact that while inhibitory processes may
predominate in response to brief acute pain, pain facilatory
process may predominate with more prolonged pain
stimuli [1]. This possibility may be important to consider
given that baroreceptor activation may trigger not
only descending pain inhibitory activity, but pain
facilatory activity as well, possibly mediated by substance
P [1,3,140,141]. It is therefore possible that chronic pain-
related increases in BP might activate baroreceptors,
triggering pain facilatory activity without adequate opposing
inhibitory activity due to chronic pain-related failure of
these latter systems (Model 3). This process would result in
a positive association between acute pain sensitivity and
resting BP occurring in the context of normal or increased
baroreceptor sensitivity. If these mechanisms are operative,
experimental studies should demonstrate that the degree of
alteration in the BP/pain sensitivity relationship across
chronic pain/pain-free subjects is accounted for by the
degree of increased temporal summation associated
with chronic pain. This possibility has also not been
directly tested.
A final, albeit indirect, mechanism could also account for
the positive relationship between resting BP and acute pain
sensitivity in chronic pain patients. That there would be a
positive link between chronic pain intensity and BP levels is
not unexpected, given the direct effects of nociceptive
stimulation on SNS arousal and BP [36,37,158]. Chronic
pain is associated not only with elevated BP [10,18,108,
163–165], but is also generally associated with elevated
negative affect (e.g. anxiety, depression; [10,181,182]).
Moreover, negative affect is often (but not always)
associated with increased acute pain sensitivity [183–186].
Given the pattern above, there might be indirect links
between increased BP and increased acute pain sensitivity
mediated by chronic pain-related negative affect (Model 4).
It would be important in future studies to rule out this latter
indirect mechanism as a potential explanation for the
alterations in the BP/pain sensitivity relationship in chronic
pain patients.
7. Methodological and interpretive issues in use
of alpha-2 adrenergic blockade methodology
The role of endogenous opioid mechanisms that may
contribute to the BP/acute pain sensitivity relationship has
been examined in several human studies using opioid
blockade. Although comparable alpha-2 adrenergic
blockade methodologies are available to examine this
possible mediator of the BP/pain sensitivity relationship in
humans (e.g. yohimbine is an FDA-approved selective
alpha-2 antagonist), no studies to date have yet employed
this methodology. Many of the animal data implicating
alpha-2 adrenergic mechanisms in descending pain
regulation in general, and in mediating the analgesic
effects of elevated BP in particular, derive from
studies using pharmacological alpha-2 adrenoceptor
blockade. Future human studies of possible noradrenergic
mechanisms will require use of alpha-2 adrenergic blockade
methodologies as well. Therefore, several interpretive
issues regarding use of this potentially important
methodology may bear consideration, particularly given
that this methodology is used less frequently than the more
common opioid blockade methodology.
Noradrenergic mechanisms in the LC interconnected
with other limbic structures underlie not only pain
responses, but emotional responses as well, particularly
anxiety [187]. Because of this, systemic pharmacologic
blockade of alpha-2 adrenergic inhibitory mechanisms,
which help modulate emotional regulatory brain structures,
results in increased negative affect even as it blocks
antinociceptive pathways. The animal studies described
previously have not addressed whether alpha
adrenergic blockade increases pain responsiveness directly
through deactivation of noradrenergic pain inhibitory
pathways (that may overlap with cardiovascular modulatory
pathways), or indirectly through increased anxiety, which is
typically associated with increased pain responsiveness
[184–186]. Limited human work indicates that
while yohimbine-induced increases in anxiety do impact
on human experimental pain responses, statistical control
of this anxiety does not eliminate yohimbine’s
hyperalgesic effects [90]. While these results suggest that
blockade-induced emotional changes do not account for the
hyperalgesic effects of alpha-2 blockade, this potential
confound is important to address in interpreting results of
such blockade studies.
It is also important to recognize that designs employing
alpha-2 adrenergic antagonists will result in blockade of
both central and peripheral alpha-2 adrenoceptors at both
presynaptic and postsynaptic sites. Interpretation of the
effects of alpha-2 antagonists with regard to implied
functioning of descending adrenergically mediated pain
modulatory pathways in the intact state therefore requires
careful consideration. It is helpful to consider the
relevant adrenergic pathways involved in descending pain
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
modulation and their overlap with brain structures involved
in BP control (see Fig. 1 above).
Alpha-2 antagonists such as yohimbine may result in
several relevant effects, including: (1) blockade of central
alpha-2 adrenoceptors in the brain structures noted above
involved in descending adrenergically mediated pain
inhibition [188–192], (2) blockade of presynaptic alpha-2
adrenergic pain inhibitory receptors on terminals of
primary afferent fibers synapsing at the spinal cord dorsal
horn [100,193–196], (3) blockade of postsynaptic alpha-2
adrenergic pain inhibitory receptors in the spinal cord
dorsal horn [197–202], (4) blockade of inhibitory alpha-2
adrenergic input into SNS preganglionic neurons
(intermediolateral cell column) resulting in increased
central sympathetic outflow [203–206], and (5) blockade
of presynaptic alpha-2 modulatory autoreceptors on
terminals of sympathetic fibers, resulting in increased
norepinephrine release from these terminals [203,207,
208]. Blockade effects as described in numbers 1–3 above
reflect blockade of the descending noradrenergic pain
pathways hypothesized to underlie the association between
resting BP and pain sensitivity. Blockade effects described
in 4–5 will result in acute increases in SNS activity, and as a
result, will produce acutely increased BP in response to the
blockade agent. If increased sympathetic outflow or
peripheral norepinephrine release were themselves either
hyperalgesic or analgesic, this could undermine the
ability to draw firm conclusions about mediators of
the relationship between BP and descending pain regulatory
mechanisms based on responses to alpha-2 adrenergic
antagonists.
Elevated SNS activity appears to be hyperalgesic only
in a subset of pathological pain conditions involving
sympathetically maintained pain mechanisms, such as
Complex Regional Pain Syndrome Types I and II
(aka RSD and Causalgia; [209]). This effect is due to
sprouting of adrenergic receptors on afferent nociceptive
fiber terminals in these conditions, resulting in ability of
circulating catecholamines and norepinephrine released
from SNS nerve terminals to directly increase nociceptive
firing [210,211]. In healthy individuals and chronic pain
sufferers without prominent catecholamine-sensitive pain
mechanisms (e.g. low back pain and many other chronic
pains), expected hyperalgesic effects of alpha-2 blockade
[89,90] can be assumed to derive from direct blockade of
central descending noradrenergic pain inhibitory pathways.
Elevated SNS activity resulting from yohimbine
administration could also in theory be analgesic, although
this action would be through indirect mechanisms.
Activation of the sympatho-adrenamedullary axis can result
in release of circulating opioid peptides from the pituitary
and adrenal medulla [212]. In principle, these
circulating opioids could have analgesic effects [212].
However, the importance of systemically circulating
opioids in producing analgesia remains unclear. For
example, although several studies report an inverse
407
association between plasma endogenous opioid levels and
pain levels [19,72,213,214], other work indicates no
relationship [73,215–219] or even a positive relationship
in some situations [220]. If increases in SNS activity
associated with alpha-2 blockade did produce analgesia, the
hyperalgesia noted previously in response to alpha-2
adrenergic blockade would represent the net effect of
SNS-mediated analgesia and direct centrally mediated
hyperalgesia. Available human studies [90,91] (unpublished
data) clearly indicate that yohimbine is hyperalgesic rather
than analgesic, despite prominent effects on increasing SNS
outflow, and this would argue for the effects of alpha-2
adrenergic blockade on central pain regulatory pathways far
outweighing any analgesic effects deriving through SNS
mechanisms. In vitro work indicates that yohimbine
specifically decreases the firing of neurons in the NRM
that are involved in both descending pain inhibition and the
BP/pain sensitivity relationship, a finding also suggesting
the relative importance of yohimbine’s effects on
descending pain inhibitory pathways in determining its’
hyperalgesic effects [221].
The relative importance of SNS-related effects of alpha-2
adrenergic blockade as opposed to its effects on descending
pain inhibitory pathways can be determined using statistical
methods. BP and norepinephrine (NE) increases due to
disinhibition of SNS activity are a primary sign of alpha-2
blockade effects on SNS outflow [222]. Therefore, analyses
of alpha-2 blockade effects on the resting BP/pain
sensitivity link controlling for blockade effects on BP and
plasma NE would permit a test of whether blockade effects
on SNS outflow confound such analyses. If alpha-2
blockade eliminates the relationship between BP and pain
sensitivity in healthy individuals even after blockade effects
on BP and NE are statistically removed, this would argue
that the SNS-related effects of blockade do not account for
the apparent alpha-2 adrenergic mediation of this
relationship. In this case, the most parsimonious
interpretation would be that the hyperalgesic effects of
alpha-2 adrenergic blockade derive from blockade of central
alpha-2 adrenergic pain inhibitory pathways overlapping
with cardiovascular modulatory pathways. Use of such
analytic strategies is recommended in future studies
using alpha-2 adrenergic blockade to test mediators of the
BP/acute pain sensitivity relationship.
We should note that although acutely elevated BP
(such as occurs with alpha-2 blockade) may be associated
with diminished pain sensitivity [51], such drug-induced BP
increases do not necessarily confound interpretation of
potential blockade studies regarding noradrenergic
mechanisms underlying the BP/pain sensitivity relationship.
For example, significant yohimbine-related BP increases do
not eliminate hyperalgesia resulting from this drug’s
administration [90,91] (unpublished data). Conceptually,
this finding is likely due to the drug’s blocking the theorized
noradrenergic pathway by which BP is associated with
analgesia. Thus, even as alpha-2 adrenergic blockade
408 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
increases BP, it may block the pathway by which these BP
increases would alter pain responses.
Another interpretive issue is whether the hyperalgesic
effects of alpha-2 adrenergic blockade specifically in
descending pain modulatory pathways are due to
presynaptic or postsynaptic effects (exclusive of
presynaptic effects on SNS autoreceptors above).
Alpha-2 adrenergic mechanisms appear to mediate
endogenous analgesia in part through presynaptic actions
at the terminals of primary afferent fibers [100,193–196].
However, alpha-2 adrenergic pain modulation also
derives from postsynaptic effects in the spinal dorsal
horn itself [197–199,202,223–225]. Thus, both
presynaptic and postsynaptic sites of action appear to
be involved in descending noradrenergic pain
modulation. It is impossible using alpha-2 adrenoceptor
blockade methodology (or any other in vivo methodology
that is not extremely invasive to the spinal cord) to
isolate whether the hyperalgesic effects of alpha-2
blockade on descending pathways derive from
presynaptic or postsynaptic sites of action. Given that
there are no known adrenergic fibers originating in the
spinal cord itself [226], descending norepinephrine
outflow from brain areas such as the LC and A5 regions
appears necessary for BP-related spinal pain modulatory
effects, whether pre- or postsynaptic in nature.
This conclusion is bolstered by evidence that chemical
lesioning of these areas eliminates BP-related analgesia
in rats [103]. Regardless of whether the hyperalgesic
effects of alpha-2 adrenergic blockade are occurring
locally in the brain (e.g. LC, RVM, A5) by inhibiting
descending norepinephrine outflow, or postsynaptically in
the dorsal horn or presynaptically at primary afferent
fiber terminals to block the effects of descending
norepinephrine activity, all of these effects ultimately
derive from the same descending noradrenergic pain
inhibitory pathways that overlap with BP regulation.
In summary, pharmacological alpha-2 adrenergic
blockade is a necessary methodology for investigating
noradrenergic mechanisms that may contribute
to expression of the BP/acute pain sensitivity
link. Interpretation of such studies may be complex.
Consideration of the issues above in the design and
interpretation of future blockade studies may be helpful.
8. Clinical implications
The review above has been generally focused on
understanding the basic mechanisms underlying important
aspects of the pain regulatory process, and how these may
be altered in chronically painful conditions. However, the
theoretical models presented may have clinical
ramifications as well. As described above, we have
previously reported a positive relationship not only between
resting BP and acute pain sensitivity, but between resting
BP and chronic pain intensity [10,18]. This latter
relationship may be intuitively obvious to chronic pain
practitioners, given the known pressor effects of clinical
pain. However, considering that there are parallel effects on
acute and chronic pain responsiveness, the theoretical
models described above would suggest that this positive
relationship reflects a failure of overlapping endogenous
inhibitory systems that would normally moderate both BP
and pain sensitivity in the context of painful stimuli. It is
surprising therefore that little research attention has been
devoted to the implications of chronic pain for
cardiovascular disease risk. The limited studies described
previously indicate that resting BP levels may be elevated in
patients with persistent pain [108,163–165], although only
one published study has directly examined the issue of
hypertension as it relates to chronic pain [172].
We hypothesized that if chronic pain-related alterations in
functional interactions between the cardiovascular and pain
regulatory systems reflect failure of overlapping systems
modulating both pain and BP, there would be an increased
prevalence of clinical hypertension in the chronic pain
population. A retrospective review was conducted on the
records of 300 randomly selected chronic pain patients
(Pain) evaluated at a tertiary care pain management center
and 300 randomly selected nonpain internal medicine
(Medicine) patients seen at the same institution.
Results revealed that over 39% of the Pain group was
diagnosed with clinical hypertension, compared to only
21% of the Medicine group (p!0.001). Analyses by gender
revealed similar group differences in males (p!0.05) and
females (p!0.001). While hypertension prevalence in the
Medicine group was comparable to national population
values (p’s>0.10), prevalence in the pain group was
significantly higher for both genders (p’s!0.005).
Similar results were obtained for antihypertensive use
(p’s !0.001). Stepwise logistic regression in the Pain
group revealed that chronic pain intensity was a significant
predictor of hypertensive status independent of the effects of
age, race/ethnicity, and parental hypertension (p’s!0.05).
These results suggested the possibility that chronic pain may
be associated with increased risk of hypertension. Future
work will have to address whether this apparent relationship
is causal, and if so, determine the direction of causality.
9. Conclusions
Functional interactions between the cardiovascular and
pain regulatory systems appear to be an important part of the
pain regulatory process. In healthy normotensive humans,
there is much evidence that baroreceptor-mediated
mechanisms are an important determinant of the adaptive
BP/pain sensitivity relationship. There is weak evidence
for partial mediation by endogenous opioids, with
opioid mechanisms possibly more important in clinically
hypertensive populations. Animal work suggests that
 S. Bruehl, O.Y. Chung / Neuroscience and Biobehavioral Reviews 28 (2004) 395–414
noradrenergic mechanisms mediated by alpha-2 adrenergic
receptors may also be important to consider, although there
is no human work directly testing this hypothesis.
The adaptive relationship between BP and acute pain
sensitivity appears to be significantly altered in chronic pain
conditions, most likely reflecting chronic pain-related
dysfunction in the pathways mediating this relationship.
There is no evidence that these dysfunctional pathways are
opioid-mediated. In the absence of opioid mechanisms,
conceptual arguments and indirect data would suggest that
chronic pain-related changes in baroreceptor sensitivity,
alpha-2 adrenergic pain inhibitory pathways, or pain
facilatory pathways may contribute to the observed changes
in the BP/pain sensitivity relationship. Preliminary clinical
research suggests that these chronic pain-related
changes could contribute to increased hypertension risk in
chronic pain sufferers.
Acknowledgements
This work was supported by grant No. R01-NS38145
from the National Institutes of Neurological Disorders
and Stroke.
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